Scientific Leadership Profile

Introduction of the principle of long-range intermolecular interactions in biosciences
[Veljkovic V. Theoretical approach to preselection of cancerogens and chemical carcinogenesis. Gordon & Breach, New York (1980)]

Initiation of the application of digital signal processing methods in analysis in genomics and proteomics and development of
the informational spectrum method for analysis of DNA and proteins [Veljkovic V. et al. IEEE Biomed. Trans. 1975;BME-32:37]

Electron-ion Interaction Potential (EIIP)

EIIP is a fundamental physical parameter which is determined ONLY by the atomic numbers in the periodic table of elements.
EIIP has been used for more than four decades for investigation of phenomena in solid state physics. EIIP has been applied as
a molecular descriptor in biosciences worldwide since 1974.

Figure 1. Some institutions applying EIIP in their work throughout the world

By 2014, more than 200 articles in peer-reviewed journals and several monographs and patents have been published worldwide,
based on the application of the EIIP molecular descriptor and ISM (PDF of 118 articles available in open sources, patents
and a list of monographs can be found at www.bioprotection.org/articles.php).

EIIP has inspired young researchers worldwide and served as the principal basis of numerous masters and doctoral theses
(46 theses available in open sources are available at www.bioprotection.org/articles.php)

Principle of long-range intermolecular interactions in a biological system

According to the concept which I formulated in 1980, the intermolecular interactions in biological systems encompass two basic steps,
(i) specific long-distance targeting of interacting molecules and (ii) chemical bond formation between interacting molecules.
The first step is determined by the selective long-range forces which are efficient at a distance longer than one linear dimension
of the interacting macromolecules (102-103 Å). These forces are responsible for recognition and targeting
between interacting molecules and directly influence efficacy of biochemical processes by controlling the number of intermolecular
productive collisions. I proposed that EIIP is the essential physical parameter determining the long-range properties of biological
molecules. Among 3300 currently used molecular descriptors, EIIP represents a unique physical property which characterizes the long-range
interactions between biological molecules [Todeschini R, Consonni V. Molecular descriptors for chemoinformatics. John Wiley & Sons (2009)].
This concept enables better understanding of the molecular interactions underlying different biological phenomena.
It also serves as the basis for development of a new generation of drugs and vaccines which prevent pathogen proteins
from recognizing the host targets. These therapeutics and vaccines are remarkably less sensitive to escape mutations than
conventional drugs and vaccines which block direct chemical binding between the pathogen and host proteins. The concept of
long-range intermolecular interactions will be applied in this project for repurposing of drugs for treatment of emerging
infectious pathogens which acquire drug resistance by the high mutation rate of the therapeutic target.

The Informational Spectrum Method (ISM)

I used the concept of the long-range intermolecular interactions, EIIP and digital signal processing (DSP) for development of ISM,
representing a virtual spectroscopy method for protein and DNA analysis. The ISM-based platform allows investigation of the
protein-protein and protein-DNA interactions, structure-function analysis of proteins, functional mapping of DNA sequences,
assessment of the biological effect of mutations, modulation of the biological function of proteins and de novo design of
peptides and proteins with the desired biological function. The ISM also served as the basis for development of the algorithm
for investigation of the functional evolution of proteins and genes. It is the only phylogenetic algorithm which allows
assessment of the biological effect of a single mutation. All these functions of the ISM platform will be used in this
project for the study of emerging pathogens and their interaction with the host.

It is important to note that proteins and DNA sequences can be subjected to ISM analysis without any prior knowledge of
their functional or structural properties (Figure 2). This unique property of ISM allows the immediate study of new
emerging pathogens. An example of this important property of ISM is the study of the pandemic influenza virus H1N1
(pH1N1): the pandemic started in May 2009 and we published an article on the molecular analysis of interaction between
the novel pH1N1 virus and the host already in June 2009 (Veljkovic V. et al. BMC Struct Biol. 2009;9:62). Another
example, by using ISM we identified a novel candidate host interactor of the Ebola virus that emerged in 2014/2015
in West Africa and assessed the effect of mutations on its interaction with the host. This article was published
in February 2015, during the Ebola outbreak (Veljkovic V. et al. Frontiers Microbiol. 2015;16:135).

Figure 2. Schematic presentation of the concept of the ISM platform

I have published three monographs and 75 articles in leading international peer-reviewed journals (a list of
references is available at www.bioprotection.org/references.php), of which 64 as the main author.